# Defining parameters to induce breadth in knockin mice expressing HIV bnAb precursors

> **NIH NIH R01** · SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE · 2020 · $577,504

## Abstract

PROJECT SUMMARY / ABSTRACT
This is a renewal R01 application to characterize an array of novel knockin (KI) mouse lines, we have created
using a previously-described gene-targeting approach, to express unmutated precursors of four well-
characterized, representative HIV-1 broadly neutralizing antibody (bnAb) lineages. Developing a preventative
vaccine remains a critical priority to end the HIV pandemic, and it is widely held that such a vaccine will need to
induce bnAb responses. While the eventual elicitation of bnAb responses in some HIV-1+ patients shows such
responses are possible, no vaccine yet can elicit them. In this regard, animal models that can systematically
identify impediments in bnAb precursor activation and maturation and iteratively test novel strategies to
overcome such hurdles, would be highly beneficial for developing a bnAb-based vaccine. Three key roadblocks
that merit further testing in such models are: i) B-cell tolerance controls, which can delete, inactivate, or modify
bnAb lineage-expressing B-cells, before and during immunization, ii) high somatic mutation levels that
accumulate in bnAbs over prolonged periods of infection, amounts prohibitive for vaccines to elicit, and whose
exact level required for function is not known, and iii) no or minimal bnAb precursor affinity for standard Env
immunogens. The overall objective of this proposal is to use novel bnAb precursor-directed immunogens to
define minimal requirements to activate, and then induce breadth in, naïve precursor KI B-cells from CH103,
CH31, CH01, and CH58 lineages (and determine if/what host controls limit both processes). The matured Abs
of these lineages are all relatively less mutated, making them more attractive vaccine candidates. Furthermore,
they target distinct Env regions, and express a different set of functional traits/neutralization profiles, thus
embody the bnAb spectrum. We hypothesize that this unique set of immunogens and models will allow us to
learn how to induce individual, immunization-directed bnAb pathways with moderate breadth, manageable
mutation levels and no (or only cryptic) self-reactivity. To test this central hypothesis, we will use a multilayered
approach where in Aim 1, we will first define to what extent naïve KI B-cells expressing CH103, CH31, CH01,
or CH58 lineage precursors are under host controls. Then, in Aim 2, we will learn how best to activate these
lineages with precursor-targeting immunogens, so they can be recruited into maturation pathways. Finally, in
Aim 3, using immunogens that can initiate maturation, we will define minimal evolutionary trajectories to desired
bnAb responses, under conditions where affinity maturation will be enhanced via cross-breeding KI mice to
those overexpressing polymerase-ζ (with elevated Ig somatic mutation rates) and/or Eµ-bcl2 (having increased
B-cell survival). Learning how to induce, and what limits bnAbs in these model settings will help define more
tractable vaccine targets and s...

## Key facts

- **NIH application ID:** 9930521
- **Project number:** 5R01AI087202-11
- **Recipient organization:** SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** Laurent Karl Verkoczy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $577,504
- **Award type:** 5
- **Project period:** 2010-04-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930521

## Citation

> US National Institutes of Health, RePORTER application 9930521, Defining parameters to induce breadth in knockin mice expressing HIV bnAb precursors (5R01AI087202-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9930521. Licensed CC0.

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